The overall objective of this proposal is to delineate prognostic markers for ZIP4-mediated cachexia in lethal pancreatic cancer (PC). Understanding these markers is critical to therapeutic interventions for PC patients suffering from muscle wasting. Cachectic muscle wasting is frequently associated with PC. Current therapies aimed at the cancer cells provide little benefit in reducing cachexia and improving patient survival, highlighting the importance of finding new prognostic biomarkers for muscle wasting and developing new therapy targeting muscle catabolism in PC. The new concept in this proposal is that ZIP4, a zinc transporter highly expressed in PC, is a key regulator of PC growth, muscle wasting and survival. We have been working on the role of ZIP4 in PC for many years. Our group is the first one to show that ZIP4 is overexpressed in a majority of PC patients (>80%) and contributes to PC pathogenesis. Silencing ZIP4 sensitizes PC cells to chemotherapy and zinc deficiency-induced apoptosis, and prolongs survival, which suggests that ZIP4 is a prognostic marker and therapeutic target for PC. Our recent studies suggest that ZIP4 mediates muscle wasting in PC. However, how ZIP4 promotes muscle wasting is not clear. In this proposal, on the basis of our recent findings we aim to determine the prognostic value of ZIP4, identify ZIP4-activated catabolic mediators, and elucidate the mechanism(s) through which ZIP4 mediates muscle wasting in PC. In our newly developed surgical xenograft mouse model, we observed that surgical removal of tumors combined with lowering ZIP4 levels in PC cells significantly improved survival and reduced body weight loss and muscle wasting. We also demonstrated that reduced ZIP4 levels in PC cells ameliorated muscle wasting due to attenuated p38 MAPK activation and subsequent atrogin1/MAFbx up regulation, which was shown previously to mediate the muscle catabolism induced by other types of tumor cells. The central hypothesis of the proposed study is that ZIP4 mediates PC-induced muscle wasting through a distinctly enhanced activation of the p38 MAPK-mediated catabolic pathway by increasing expression and release of specific heat shock proteins and this ZIP4-enhanced cachexia pathway could serve as a prognostic marker for this dismal disease. Three specific aims are proposed: We will evaluate the prognostic values of ZIP4 and related catabolic pathway in PC by examining the correlation of ZIP4 in resected tumors with serum Hsp70/90 levels, p38 MAPK-activated catabolic pathway in muscles and clinical outcome (survival) of PC patients. We will determine whether PC induces muscle wasting in two independent mouse models of PC cachexia through ZIP4-dependent expression/release of Hsp70 and Hsp90. We will delineate the mechanisms of PC induced muscle wasting through Hsp70/90 activation of p38 MAPK-mediated muscle catabolism. ZIP4-induced cachexia represents a novel signaling pathway impacting PC growth and survival. The proposed studies will help define the mechanism regulating this oncogenic axis and evaluate the prognostic value of the ZIP4-cachexia axis in PC. This study will have an immediate impact for PC patients.